The Toxic Effects And Mechanism Of Organophosphate Esters And Per(Poly-) Fluoroalkyl Substances On Hepatocytes

In recent years,Triphenyl phosphate(TPHP)and its hepatic metabolites Diphenyl phosphate(DPHP),Perfluorooctane sulfonic acid(PFOS)and its substitute Sodium ρ-perfluorous nonenoxybenzene sulfonate(OBS)is the most frequently detected Organophosphate esters(OPEs)and Per-and poly-fluoroalkyl substances(PFASs)in environmental media and humans.It has been shown that the liver is the main enrichment or metabolism organ for OPEs and PFASs,but there is a paucity of studies related to the toxic effects and molecular mechanisms of OPEs and PFASs on hepatocytes.In this experiment,human normal hepatocytes(L02)were used to study the damage of TPHP,DPHP,PFOS and OBS on hepatocytes at the cellular level,and the systemic toxicity caused by the target pollutants on hepatocytes was comprehensively analyzed and compared by transcriptome sequencing(RNA sequence,RNA-seq).In addition,the toxicity and mechanisms of TPHP in liver were verified at the in vivo level.The main findings of the study are as follows:(1)TPHP exhibited more potent hepatocyte toxicity than DPHP.Insulin resistance was one of the most significant toxicities induced by TPHP in hepatocytes,and TPHP exposure significantly reduced insulin-stimulated glucose uptake and glycogen synthesis and significantly upregulated m RNA of endoplasmic reticulum stress marker genes,whereas no significant changes were observed after DPHP exposure.The specific inhibitor of endoplasmic reticulum stress,4-phenylbutyric acid(4-PBA),significantly reversed the toxic effects induced by TPHP.TPHP exposure induced stronger insulin resistance through endoplasmic reticulum stress compared to DPHP.(2)TPHP at high concentrations(80 mg/kg)significantly reduced body weight and liver glycogen content in C57BL/6J mice and caused a significant increase in postprandial glucose,which interfered with glucose metabolism in the body;TPHP exposure caused significant upregulation of m RNA of endoplasmic reticulum stress-related genes in the liver of experimental mice.The addition of 4-PBA reversed the toxic effects induced by TPHP exposure,so TPHP exposure was able to induce endoplasmic reticulum stress and insulin resistance in the mouse liver.(3)OBS has a hepatocytotoxic mechanism that is not identical to PFOS.Hepatocyte toxicity induced by PFOS and OBS is focused on pathways related to steroid synthesis and ECM-receptor interactions,respectively.Cholesterol(TC)levels were significantly decreased after PFOS exposure,whereas m RNA levels of extracellular matrix marker genes were significantly increased after OBS exposure.OBS caused higher levels of L02 apoptosis,iron death levels,and higher levels of pro-inflammatory cytokines than PFOS.All of these indicate that OBS is more hepatocytotoxic than PFOS and is not an ideal alternative to PFOS.